1. We have shown that methotrexate polyglutamates (with one to four additional glutamates) are formed in a dose-dependent and time dependent manner, and their formation is associated with prolonged inhibition of DNA synthesis in human tumor cells. 2. We have examined the interaction of Pala and 5-FU with respect to their synergistic effects on thymidylate synthetase. 3. Studies have been completed on the kinetics, substrate specificity, and allosteric regulation of dCMP hydrolyase from human spleen and from leukemic leukocytes. 4. We have pursued investigations of the utility of test doses of methotrexate as predictors for the pharma cokinetics of high dose MTX in patients with altered renal function. 5. We have confirmed that melatonin decreases the incidence of DMBA induced breast cancer in prepubertal rats, that it partially corrects the increased rate in pinealectomized animals, and that these effects may be mediated by a drop in prolactin levels.